The active component of marijuana, delta9-tetrahydrocannabinol (THC) exerts its psychotropic effects via activation of the cannabinoid 1 (CB1) receptors. Modulation of dopamine (DA) release in the striatal complex is thought to underlie the euphoric and reinforcing properties of drugs; moreover, CB1 receptors located in the striatum are likely to mediate these effects of THC, although the mechanism is unknown. Our preliminary data show that CB1 receptor activation modulates DA release indirectly, via regulation of GABA release, and possibly that of glutamate. The main hypothesis is that CB1 receptors that are located on GABAergic and glutamatergic terminals exert their effects by suppressing the release of the transmitters from these terminals, which ultimately results in the modulation of DA release. To test this hypothesis, DA release will be monitored voltammetrically in striatal slices in the presence of CB1 agonists and antagonists, then in the presence of GABA or glutamate antagonists. Further studies using whole-cell recording and fluorescence imaging will examine whether hydrogen peroxide, which mediates GABA- and glutamate-dependent modulation of striatal DA release under normal conditions, plays a role in regulation by CB1 receptors. [unreadable] [unreadable] [unreadable]